Prostate cancer is the most common malignancy and the second leading cause of cancer mortality amongst men in the Western world. In the USA, there is an estimated incidence of 217,730 cases and 32,050 deaths in 2010. Up to 40% of men diagnosed with prostate cancer will eventually develop metastatic disease, and although most respond to initial medical or surgical castration, progression to castration resistance is universal. The average survival for patients with castration-resistant prostate cancer is 2-3 year[1]. It continues to be a major cause of cancer-related morbidity and mortality, and there is an urgent need for new treatments.
Oncolytic Virotherapy.
Oncolytic virotherapy is a novel strategy using viruses, either naturally occurring or genetically modified, to selectively target and destroy tumor cells while leaving surrounding non-malignant cells unharmed [2]. Our preliminary data show that ΔNS1 RSV, not wt RSV, specifically kills prostate cancer cells (LN Cap cells) (FIG. 2), and ΔNS1 RSVNS1 protein functions as an anti-apoptotic factor and deletion of NS1 restores the apoptotic pathway in tumor cells.
Biology of RSV NS1 Protein.
RSV genome contains individual genes for ten viral proteins [3]. The transcription of RSV genes is polar, with the promoter-proximal genes being transcribed more frequently than the promoter-distal ones. The NS1 gene is promoter-proximally located at the 3′ end of the viral genome and therefore its mRNA is the most abundant of the RSV transcripts in a linear start-stop-restart mode[4] (FIG. 1). NS1 protein is referred to as nonstructural since it has not been detected in RSV particles. NS1 is exclusively found in RSV-infected cells. Our group, along with others, has found that NS1 can counter the type I IFN signaling during RSV infection[5, 6], implying that NS1 plays a direct role in inhibiting the host's innate immune response.
ΔNS1 RSV Induces Apoptosis in Human Prostate Cancer Cells.
Evasion from apoptotic cell death unregulated cell proliferation and eventual tumor development is one of the hallmarks of oncogenic cell transformation. We found that ΔNS1 RSV selectively induces apoptosis in tumor cells as we demonstrated in our previous patent application Ser. No. 12/925,886, and also generated CPE in prostate cancer cells (FIG. 2), suggesting that multiply mechanism-mediated cell death participates in the anti-tumor effect of ΔNS1 RSV.
RSV can be rendered nonpathogenic by mutating the NS1 gene so that it no longer inhibits IFN release, which attenuates viral infection in normal cells. However, these nonpathogenic RSV, ΔNS1 RSV, are still oncolytic because tumor cells are defective in their ability to produce and respond to IFN and, therefore, efficiently support the propagation of ΔNS1 RSV and ΔNS1 RSV kills tumor cells.